WO-95-26953 Publication discloses that the compounds of the following formula (P-1), etc. have selective antagonistic effects on 5-HT.sub.4 receptors, and are useful for the prophylaxis or treatment of various gastrointestinal diseases, etc. ##STR3##
wherein R.sub.1 is a halogen atom, R.sub.2 is a lower alkoxy group, etc., m is 1 or 2, p is an integer of 1 to 6, B is a group of the formula: EQU --N(R.sub.4)--X.sub.1 --R.sub.5, EQU --N(R.sub.4)--X.sub.2 --N(R.sub.6)(R.sub.7), EQU --X.sub.1 --N(R.sub.8)(R.sub.9),
or EQU --Het
(X.sub.1 is CO, CS or SO.sub.2, X.sub.2 is CO or CS, R.sub.4 is a hydrogen atom, a lower alkyl group, etc., R.sub.6 and R.sub.7 are a lower alkyl group, etc., or R.sub.6 and R.sub.7 may combine together with the adjacent nitrogen atom to form a ring, R.sub.8 and R.sub.9 are a lower alkyl group, etc., or R.sub.8 and R.sub.9 may combine together with the adjacent nitrogen atom to form a ring, Het is a 5- or 6-membered, mono- or bicyclic heterocycle group having an amide or urea in the ring and having 1-5 heteroatom(s) selected from oxygen atom, sulfur atom and nitrogen atom, and the definitions for some substituents are omitted) PA0 (in which R.sup.1 is a halogen atom, PA0 R.sup.2 is a hydrogen atom or a lower alkyl group, PA0 R.sup.3 is a hydrogen atom, a lower alkyl group, or a lower alkanoyl group, PA0 R.sup.4 is a hydrogen atom or a lower alkyl group, PA0 R.sup.5 and R.sup.6 are the same or different and each a hydrogen atom or a lower alkyl group, and PA0 n is 1,2 or 3), PA0 (in which Z is --CO--, --CS-- or --SO.sub.2 --, PA0 Q.sup.1 and Q.sup.2 are the same or different and each a hydrogen atom, a lower alkyl group, a cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted phenyl-lower alkyl group, or Q.sup.1 and Q.sup.2 may combine together with the nitrogen atom to which they bond to form a pyrrolidine ring, a piperidine ring, a hexahydroazepine ring, a morpholine ring, a thiomorpholine ring, or a piperazine ring having optionally a lower alkyl or benzyl substituent on the other nitrogen atom); EQU --CO--R.sup.7 (A-2) PA0 (in which R.sup.7 is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkyl group being substituted by a hydroxy, lower alkoxy or lower alkoxycarbonyl group, or a substituted or unsubstituted phenyl group); EQU --(CH.sub.2).sub.p --CH(R.sup.8)--COR.sup.9 (A-3) PA0 (in which p is 0, 1, 2, 3, 4 or 5, PA0 R.sup.8 is a hydrogen atom or a lower alkyl group, and PA0 R.sup.9 is a lower alkyl group or a lower alkoxy group), and also provides an intermediate of the following formula (II) (hereinafter, occasionally simply referred to as the intermediate (II)) or an acid addition salt thereof: ##STR8## PA0 (a) in the formula (A-1), Q.sup.1 is a hydrogen atom, a C.sub.1 -C.sub.4 alkyl group, or a C.sub.3 -C.sub.7 cycloalkyl group, Q.sup.2 is a hydrogen atom, a C.sub.1 -C.sub.4 alkyl group, a C.sub.3 -C.sub.7 cycloalkyl group, a phenyl group being optionally substituted by a halogen, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy group, or a benzyl group being optionally substituted by the same substituents as above, or Q.sup.1 and Q.sup.2 may combine together with the nitrogen atom to which they bond to form a pyrrolidine ring, a piperidine ring, a hexahydroazepine ring, a morpholine ring, or a piperazine ring having optionally a C.sub.1 -C.sub.4 alkyl or benzyl substituent on the other nitrogen atom, or PA0 (b) in the formula (A-2), R.sup.7 is a hydrogen atom; a C.sub.1 -C.sub.4 alkyl group; a C.sub.1 -C.sub.4 alkyl group being substituted by a C.sub.1 -C.sub.4 alkoxy or C.sub.1 -C.sub.4 alkoxycarbonyl group; a C.sub.1 -C.sub.4 alkoxy group; a C.sub.1 -C.sub.4 alkoxycarbonyl group; or a phenyl group being optionally substituted by 1 to 3 groups selected from the group consisting of a halogen atom, a C.sub.1 -C.sub.4 alkyl group, a C.sub.1 -C.sub.4 alkoxy group and an amino group, or PA0 (c) in the formula (A-3), R.sup.8 is a hydrogen atom or a C.sub.1 -C.sub.4 alkyl group, R.sup.9 is a C.sub.1 -C.sub.4 alkyl group or a C.sub.1 -C.sub.4 alkoxy group, and p is 0, 1 or 2, PA0 (in which Z is --CO--, --CS-- or --SO.sub.2 --, Q.sup.11 and Q.sup.21 are the same or different and each a methyl group, an ethyl group, a propyl group, or an isopropyl group, or Q.sup.11 is a hydrogen atom, and Q.sup.21 is a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, or a substituted or unsubstituted phenyl group (said substituents may be a halogen atom, a C.sub.1 -C.sub.4 alkyl group or a C.sub.1 -C.sub.4 alkoxy group), or Q.sup.11 and Q.sup.21 may combine together with the nitrogen atom to which they bond to form a pyrrolidine ring or a morpholine ring); EQU --CO--R.sup.71 (A.sup.1 -2) PA0 (in which R.sup.71 is a hydrogen atom, a methyl group, an ethyl group, a propyl group, a methoxy group, an ethoxy group, a C.sub.1 -C.sub.4 alkyl group being substituted by a methoxy, ethoxy, methoxycarbonyl, or ethoxycarbonyl group, or a substituted or unsubstituted phenyl group (said substituents may be 1 to 3 groups selected from a halogen atom, a C.sub.1 -C.sub.4 alkyl group, a C.sub.1 -C.sub.4 alkoxy group and an amino group); EQU --(CH.sub.2)p'--CH(R.sup.81)--COR.sup.91 (A.sup.1 -3) PA0 (in which p' is 0, 1 or 2, R.sup.81 is a hydrogen atom, a methyl group, or an ethyl group, R.sup.91 is a methyl group, an ethyl group, a methoxy group, or an ethoxy group).
The compounds of the present invention of the formula (I) as mentioned below are distinguished from the compounds of the formula (P-1) having an amide-bond and a piperidine moiety bonded each other via an alkylene, and further having different substituents at the 1-position of the piperidine ring.
In addition, EP-A-445862 (=JP-A-04-211685) Publication discloses that N-(4-piperidinyl)(dihydrobenzofuran or dihydro-2H-benzopyran)carboxamide derivatives of the following formula (P-2) exhibit gastrointestinal motility stimulation properties. ##STR4##
wherein A is a group of the following formula: EQU --CH.sub.2 --CH.sub.2 -- (a-1); EQU --CH.sub.2 --CH.sub.2 --CH.sub.2 -- (a-2);
or EQU --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 -- (a-3);
R.sub.1 is a hydrogen atom or a halogen atom, R.sub.2 is a hydrogen atom, an amino group, etc., R.sub.3 is a hydrogen atom, a C.sub.1-6 alkyl group, etc., L is a C.sub.3-6 cycloalkyl group, etc., L is a group of the formula: EQU --Alk--R.sub.4 (b-1); EQU --Alk--X--R.sub.5 (b-2); EQU --Alk--Y(C.dbd.O)--R.sub.7 (b-3);
or EQU --Alk--Y(C.dbd.O)--NR.sub.9 R.sub.10 (b-4);
(each Alk is a C.sub.1-6 alkanediyl group, R.sub.4 is a hydrogen atom, a cyano group, a C.sub.1-6 alkysulfonylamino group, a C.sub.3-6 cycloalkyl group, a C.sub.5-6 cycloalkanone group, an aryl group, a di(aryl)-methyl group, or Het (Het is a 5- or 6-membered heterocyclic group having 1, 2, 3 or 4 heteroatom(s) selected from oxygen, sulfur and nitrogen, etc.), R.sub.5 is a hydrogen atom, a C.sub.1-6 alkyl group, etc., X is O, S, SO.sub.2 or NR.sub.6 (R.sub.6 is a hydrogen atom, a C.sub.1-6 alkyl group or an aryl group), R.sub.7 is a hydrogen atom, a C.sub.1-6 alkyl group, etc., Y is NR.sub.8 or a direct bond (R.sub.8 is a hydrogen atom, a C.sub.1-6 alkyl group or an aryl group), R.sub.9 and R.sub.10 are independently a hydrogen atom, a C.sub.1-6 alkyl group, etc., or R.sub.9 and R.sub.10 may combine together with the nitrogen atom to which R.sub.9 and R.sub.10 bond to form a pyrrolidinyl or piperidinyl ring being optionally substituted with a C.sub.1-6 alkyl group, an amino group, etc., or R.sub.9 and R.sub.10 may combine together with the nitrogen atom to which R.sub.9 and R.sub.10 bond to form a piperazinyl or 4-morpholinyl ring being optionally substituted with a C.sub.1-6 alkyl group, and the definitions for some substituents are omitted).
Among the compounds of the above formula (P-2), when R.sub.4 is Het and said Het is a piperidine, the compound of the formula (P-2) may theoretically be overlapped with some of the compounds of the formula (I) of the present invention, but said EP Publication exemplifies as such compounds only a compound of the formula (P-2') (Compound 57): ##STR5##
The compound of the above formula (P-2') has an unsubstituted piperidine bonded at the 1-position thereof, which is quite different from the compounds (I) of the present invention, because the present compound (I) has a piperidine ring having a specific substituent (i.e., A) at the 1-position of said piperidine ring, and said piperidine ring is bonded at the 4-position thereof, as described below.
At the present, cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)-propyl]-3-methoxy-4-piperid inyl]-2-methoxybenzamide (general name; cisapride, cf., Merck Index, 12 ed., 2377 (1996)) has widely been used in the clinical field as a gastrointestinal motility enhancer or as a gastrointestinal prokinetic agent. Recently, 5-HT.sub.4 receptors were found during the studies on serotonin receptors being participated in gastrointestinal motility stimulation by metoclopramide or cisapride, and it has been confirmed that these benzamide derivatives enhance the gastrointestinal motility by stimulating 5-HT.sub.4 receptors (cf., J. Pharmacol. Exp. Ther., 1990, 252, 1378; J. Pharmacol. Exp. Ther., 1991, 257, 781). Thus, a compound stimulating 5-HT.sub.4 receptors being widely distributed throughout the gastrointestinal organs may be expected to enhance the gastrointestinal motility, but cisapride as mentioned above shows disadvantageously inhibitory effects on the central nervous system based on the antagonistic activity against dopamine D.sub.2 receptors, or side effects on the heart. Therefore, it is difficult to use cisapride in the clinical field. Besides, there is a growing tendency to increase patients being suffering from symptoms associated with gastrointestinal motor disorders due to the complicated society and aging society, and under these circumstances, it has been strongly desired to develop an excellent gastrointestinal prokinetic agent.